This phase I/II trial tests the safety, side effects, best dose, and efficacy of FOLFOX and bevacizumab in combination with botensilimab and balstilimab (3B-FOLFOX) in treating patients with microsatellite stable (MSS) colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Chemotherapy drugs, such as FOLFOX, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Balstilimab and botensilimab are in a class of medications called monoclonal antibodies. They bind to proteins, called PD-L1 and CTLA-4, which is found on some types of tumor cells. These PD-1 and CTLA-4 proteins are known to affect the body's defense mechanism to identify and fight against tumor cells. The combination of these drugs may lead to improved disease control and outcomes in patients with MSS metastatic colorectal cancer.
PRIMARY OBJECTIVES: I. To assess the safety and tolerability of leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX) bevacizumab, balstilimab and botensilimab at each dose level in order to inform the recommended phase 2 dose (RP2D). (Phase I) II. To assess the overall response rate of FOLFOX bevacizumab, balstilimab at 240 mg and botensilimab at 25 mg and 75 mg (depending on dose level). (Phase II) SECONDARY OBJECTIVES: I. To assess the overall response rate, progression-free survival (PFS), and overall survival (OS) of FOLFOX bevacizumab, balstilimab at 240 mg and botensilimab at 25 mg and 75 mg (depending on dose level). (Phase I) II. To estimate the median PFS and median OS associated with FOLFOX bevacizumab, balstilimab at 240 mg and botensilimab at 25 mg and 75 mg botensilimab (depending on dose level). (Phase II) III. To estimate the duration of response associated with FOLFOX bevacizumab, balstilimab at 240 mg and botensilimab at 25 mg botensilimab and 75 mg (depending on dose level). (Phase II) IV. To evaluate the safety/feasibility of FOLFOX bevacizumab, botensilimab, and balstilimab, through the assessment of adverse events. (Phase II) V. To describe the rate of secondary resection in all arms of treatment and summarize their outcome in terms of disease relapse post-surgery. (Phase II) CORRELATIVE OBJECTIVE: I. Evaluate potential circulating biomarkers of response, resistance, activity, and toxicity. OUTLINE: This is a phase I, dose-escalation study of botensilimab followed by a randomized phase II study. PHASE I: Patients receive FOLFOX, bevacizumab, balstilimab, and botensilimab intravenously (IV) on study. Patients undergo an x-ray, computed tomography (CT) scan, positron emission tomography (PET) scan, and/or magnetic resonance imaging (MRI) throughout the trial. Patients also undergo blood sample collection during screening and on study. PHASE II: Patients are randomized to 1 of 2 arms. ARM I: Patients receive FOLFOX, bevacizumab and balstilimab IV with botensilimab IV at a lower dose on study. Patients undergo an x-ray, CT scan, PET scan, and/or MRI throughout the trial. Patients also undergo blood sample collection during screening and on study. ARM II: Patients receive FOLFOX, bevacizumab and balstilimab IV with botensilimab IV at a higher dose on study. Patients undergo an x-ray, CT scan, PET scan, and/or MRI throughout the trial. Patients also undergo blood sample collection during screening and on study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Given IV
Given IV
Undergo a blood sample collection
Given IV
Undergo a CT scan
Given IV
Given IV
Undergo MRI
Given IV
Undergo a PET scan
Undergo an x-ray
City of Hope Medical Center
Duarte, California, United States
Incidence of adverse events (phase I)
Toxicity, graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. A dose limiting toxicity is a toxicity that occurs in the first 6 weeks of treatment with 3B-FOLFOX and that is attributed at least as possibly related to the study drugs
Time frame: Up to 6 weeks
Overall response (phase II)
As assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Will examine the proportion of the liver metastasis among the 60 enrolled patients and carry out subgroup analysis for overall response for patients with and without liver metastasis.
Time frame: Up to 5 years
Overall response (phase I)
Assessed by RECIST v 1.1. Will examine the proportion of the liver metastasis among the 60 enrolled patients and carry out subgroup analysis for overall response for patients with and without liver metastasis.
Time frame: Up to 5 years
Progression-free survival (PFS) (phase I)
Kaplan-Meier curve will be used to assess the PFS. Median survival and the 95% confidence interval (CI) will be reported. The effect of the higher botensilimab dose (75mg versus \[vs\] 25mg) will be estimated by the hazard ratio (HR) in a Cox proportional hazard model with and without adjustment for clinically relevant covariates. Will examine the proportion of the liver metastasis among the 60 enrolled patients and carry out subgroup analysis for PFS for patients with and without liver metastasis.
Time frame: Time to disease progression/ relapse or death as a result of any cause, assessed up to 5 years
Overall survival (OS) (phase I)
Kaplan-Meier curve will be used to assess the OS. Median survival and the 95% CI will be reported. The effect of the higher botensilimab dose (75mg vs 25mg) will be estimated by the HR in a Cox proportional hazard model with and without adjustment for clinically relevant covariates. We will examine the proportion of the liver metastasis among the 60 enrolled patients and carry out subgroup analysis for OS for patients with and without liver metastasis.
Time frame: Time to death as a result of any cause, assessed up to 5 years
PFS (phase II)
Kaplan-Meier curve will be used to assess the PFS. Median survival and the 95% CI will be reported. The effect of the higher botensilimab dose (75mg vs 25mg) will be estimated by the HR in a Cox proportional hazard model with and without adjustment for clinically relevant covariates. Will examine the proportion of the liver metastasis among the 60 enrolled patients and carry out subgroup analysis for PFS for patients with and without liver metastasis.
Time frame: Time to disease progression or death as a result of any cause, assessed up to 5 years
OS (phase II)
Kaplan-Meier curve will be used to assess the OS. Median survival and the 95% CI will be reported. The effect of the higher botensilimab dose (75mg vs 25mg) will be estimated by the HR in a Cox proportional hazard model with and without adjustment for clinically relevant covariates. We will examine the proportion of the liver metastasis among the 60 enrolled patients and carry out subgroup analysis for OS for patients with and without liver metastasis.
Time frame: Time to death as a result of any cause, assessed up to 5 years
Duration of response (phase II)
Time frame: Time to progression or death, starting at the time when a response is experienced, assessed up to 5 years
Incidence of adverse events (phase II)
Toxicity, graded according to the NCI-CTCAE v5.0.
Time frame: Up to 5 years
Surgical resection (phase II)
Time frame: Up to 5 years
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